Of the 9 million human beings with NIDDM, over 30%, at least 3 million people, will have an insular amyloidotic lesion that contributes to the severity of diabetes in many people and is the sole cause of diabetes in others. The prevalence of the insular amyloidotic lesion and its contribution to NIDDM have never been established in human beings, although the lesion has been well characterized in diabetic Macaca nigra. In monkeys, it causes formation of islet cell antibodies (ICA). Preliminary results on 800 human beings with NIDDM showed that greater than 35% of the patients over 40 years of age had ICA, presumably from a similar lesion. Over 2000 NIDDM patients will be assessed for ICA. Experimental and control groups of ICA-positive (ICA+) and ICA- diabetic patients and nondiabetic controls, adjusted for age, sex, and ideal body weight, will be examined with oral glucose tolerance tests. Those with ICA should have impaired insulin secretion and glucose clearance. The ICA+ diabetic subpopulation, when examined by human lymphocyte antigen typing, could be homogenous enough to reveal specific genetic markers. Familial tendencies toward ICA and diabetes will be assessed in relatives of ICA+ diabetics. Pancreas samples will be obtained from patients when they die. Correlation of islet cell deterioration and amyloid deposition with the ICA and the metabolic status will allow prospective establishment of the prevalence of this lesion in NIDDM. The lesion could constitute a major problem in clinical treatment of the older NIDDM population. Other aspects will be studied at the biochemical level. The ICA selectively stain only some of the substrate islet cells. Specific immunogenic antigens unique to these cells must have been released, to cause formation of ICA. These islet antigenic proteins or glycoproteins will be isolated and characterized. Islet amyloid is chemically similar to secondary systemic amyloid A (AA); aggravation within the islet probably causes deposition of AA from its circulating precursor (SAA). The level of circulating amyloid-degrading factor (ADF) may also affect AA availability for deposition. Both the levels and the SAA/ADF ratio will be evaluated in ICA+ and ICA- nondiabetic and diabetic humans.